Light-Directed Method for Detecting and Aiding Further Evaluation of Abnormal Mucosal Tissue

ABSTRACT

In a light-directed method of identifying abnormal mucosal tissue, any suspect sites revealed by a light that selectively aids in visualizing abnormal tissue are marked with a dye facilitate further evaluation of the suspect tissue.

This invention relates to methods for detecting and aiding theevaluation of abnormal mucosal tissue.

In a more specific respect, the invention concerns a light-directedmethod, in which mucosal tissue indicated as abnormal by illuminating agross anatomical area with light that selectively enhances visualizationof abnormalities and before discontinuing illumination by selectivelight, any suspect abnormal sites so-located are then marked with atissue marking agent, to assist in further evaluation of theseabnormalities by any of a variety of techniques, to determine whethersuch suspect sites have serious pathology.

In still another and more particular respect the invention relates tosuch a method, in which the marking agent contains a staining dye whichselectively indicates whether such a suspect site has serious pathology.

BACKGROUND OF THE INVENTION

Patients who delay in obtaining a cancer consultation for at least twomonths have significantly higher relative hazards of death than dopatients with a shorter delay. Thus, if patients are more regularlysubjected to effective cancer screening, the mortality risks of cancerwould be reduced.

Abnormal mucosal tissue, which may harbor tumor phenotypes, and whichmay indicate the presence of or the eventual development of invasivecancer can be visually identified and located in realtime in vivo usingselective light examinations, which are admirably suited for rapid andinexpensive screening carried out as an adjunct to routing dentalexaminations. Illustratively, for example, U.S. Pat. Nos. 5,179,938 and5,329,938, incorporated herein by reference, describe instrumentsequipped with a chemiluminescent light source which radiates in thevisible green, blue and red spectrums, with spectral peaks at 450, 550and 580 nm. Under such illumination, with normal ambient lightsuppressed, abnormal mucosal tissue appears white. Illustratively, suchselective light devices for practicing such in vivo examinations arecommercially available under the registered trademark VIZILITE® fromZila Pharmaceuticals, Inc., Phoenix, Ariz., USA.

Once an abnormal mucosal site has been located by selectivelight-directed screening, further diagnostic/prognostic procedures arethen indicated to determine whether the suspect abnormal site hasserious pathology. For example, biopsy of the suspect site, followed byconventional histological procedures or more recently developed“molecular analysis” techniques, are then performed to determine whetherthe abnormal tissue is cancerous or is in the progression pathway tolikely develop invasive cancer. These molecular analysis techniques aredisclosed in my International Application PCT/US02/32073 (WP 03/057918A1), incorporated herein by reference.

While the selective light examinations can successfully identify andlocate suspect mucosal tissue sites, the fact that the examinationreveals these sites in real time, i.e., only while the selective lightis directed onto the mucosal tissues, may make it difficult, after theselective light illumination is discontinued, to again locate and/ordelineate such abnormal tissue sites for the purpose of further visualevaluation and, if indicated, conducting such furtherdiagnostic/prognostic procedures, e.g., excision of histology ormolecular analysis tissue samples of the abnormal tissue and/or ofneighboring normal tissue, for comparison with the abnormal tissue.

To minimize such difficulty in locating the abnormal and/or normaltissue, it would be highly desirable to provide a selectivelight-directed diagnostic/prognostic method which incorporates aprocedure for marking the location or delineating the abnormal tissuewhile the selective light is still directed upon the tissue, such thatthe abnormal tissue remains apparent after the selective lightillumination is discontinued.

BRIEF DESCRIPTION OF THE INVENTION

Briefly, I provide a light-directed method for detecting abnormalmucosal tissue which includes the steps of locating suspect mucosaltissue sites in a gross anatomical area, by illuminating the tissue withlight that selectively enhances visualization of mucosal abnormalities,and marking such suspect sites to assist in further evaluation thereof,by applying a marking agent comprising a tissue-staining dye to suchsuspect sites.

In a further embodiment, the invention includes the use of a markingagent dye that both marks and delineates the extent of such suspecttissue.

In still another embodiment of the invention, I use a marking agent dyewhich selectively marks abnormal tissue, which may be cancerous orprecancerous.

In a more specific embodiment, the invention includes the step ofapplying the marking agent by using a swab carrying a liquid markingagent containing the marking agent dye.

In another specific embodiment, the invention includes the step ofmarking the abnormal tissue by rinsing the gross anatomical area with aliquid containing the marking agent dye, using a dye which itselfselectively marks abnormal tissue.

In still another embodiment of the invention, I employ a marking agentdye to a suspect abnormal site which dye, itself, further indicateswhether such site has serious pathology.

In a still further embodiment the invention relates to the use of astaining dye in formulating a marking agent for use by applying the dyeto suspect tissue identified by illuminating the tissue in a grossanatomical area with light that selectively enhances visualization ofmucosal abnormalities.

These and other embodiments of my invention will be apparent to thoseskilled in the art from the following detailed illustrative description.

DETAILED DESCRIPTION OF THE INVENTION

The following examples illustrate the invention and enable those skilledin the art how to practice the invention and identify the presentlypreferred embodiments thereof. As such, this description is not alimitation on the scope of the invention, which is expressed only by theappended claims.

Example 1

This example illustrates the step of detecting abnormal mucosal tissuewith a light that aids in selectively visualizing abnormal tissue in theoral cavity.

A routine visual examination of the oral cavity is made, noting thepresence of any lesions on the attached gingiva, the buccal mucosa, thefloor of the mouth, the hard and soft palate and the dorsal, lateral andventral tongue.

The patient is then instructed to rinse the mouth with a 1% acetic acidsolution for up to one minute and then expectorate.

The chemiluminescent light source described in the Lonky U.S. Pat. No.5,329,938, commercially available under the registered trademarkVIZILITE®, is activated by bending the flexible outer capsule, breakingthe brittle inner vial. The capsule is then shaken and it is insertedinto the retractor.

The ambient lights are then dimmed.

The visual examination of the oral cavity is then repeated using theillumination provided by the light source, looking for lesions or othersuspect tissue sites which appear white.

Example 2

This example illustrates the step of marking any suspect tissue sitesidentified in Example 1, by applying a tissue-staining dye marking agentto the suspect sites.

A swab is saturated with a toluidine blue 0 dye substance. This dyesubstance is disclosed in my published International ApplicationWO99/25388, and is commercially available under the trademark ZilaTolonium Chloride™.

While the selective light is still being applied to the oral cavity, thedye is applied with the swab directly to each of the suspect sitesidentified by the light examination. The dye marks the tissue at thesuspect site, marking the tissue dark blue, thus preserving the locationof such suspect sites after the selective light illumination of Example1 is removed.

The marked locations can then be evaluated for the presence of seriouspathology, e.g. cancer or precancer. For example, the marked sites canthen be sampled by excision, e.g., by a standard punch biopsy, to obtaintissue for subsequent examination, e.g., by standard histology ormolecular analysis.

Example 3

Instead of the dye used in Example 2, other dyes which selectively stainsuspect mucosal tissue in vivo are employed to mark the suspect sitesidentified in Example 1. For example, dyes such as those disclosed in mypublished International Applications Nos. WO02/03048 (methylene blue),WO2/202149 (rhodamine) and the dyes disclosed in the publishedInternational Applications by Pomerantz, WO97/26018 (certain otheroxazine and thiazine dyes), and Tucci, WO93/08847 (toluidine blueO+peroxide) are employed. These published International Applications areincorporated herein by reference.

Similar results are obtained.

Example 4

Instead of applying the marking agent with a swab, the patient isdirected to rinse the oral cavity with a liquid solution of the dyes ofExamples 2 and 3. Similar results are obtained.

Example 5

After completing the procedures of Examples 1 and 2, 3 or 4, the patientis re-examined in two weeks, using the same procedures. This delayallows suspect tissue that may not have serious pathology, such assimple abrasions, cuts, non-serious lesions such as apthous ulcers, etc.to heal. If this re-examination reveals the same suspect sites, then theprobability of serious pathology is increased.

Example 6

The procedures of Examples 1-4 are repeated, except that the grossanatomical areas examined includes the anal and vaginal mucosal tissues.

Similar results are obtained.

Example 7

The cationic supravital dyes employed in Examples 2 and 3 willselectively enter the mitochondria of cancerous and precanceroustissues. The marking of suspect mucosal tissue sites by these dyes isfurther indication of serious pathology, such that the delayedre-examination of Example 5 before tissue sampling for histology ormolecular analysis may not be necessary.

1. A light-directed method for detecting abnormal mucosal tissue, saidmethod comprising the steps of: (a) locating suspect abnormal mucosaltissue sites in a gross anatomical area, by illuminating said tissue invivo with light that selectively enhances visualization of mucosalabnormalities; and (b) marking such suspect sites to assist in furtherevaluation thereof, by applying a marking agent comprising atissue-staining dye to such suspect abnormal tissue sites.
 2. The methodof claim 1 in which said marking agent both marks and delineates suchsuspect tissue sites.
 3. The method of claim 1 in which said markingagent selectively marks abnormal tissue sites.
 4. The method of claim 1,in which said marking agent is applied to the suspect abnormal sites bya swab carrying a liquid marking agent containing said dye.
 5. Themethod of claim 1, in which said marking agent is applied to suchsuspect abnormal sites by rinsing said gross anatomical area with aliquid marking agent containing said dye.
 6. The method of claim 3, inwhich the selective staining of a suspect abnormal sites indicateswhether such site has serious pathology.
 7. The use of a staining dye informulating the marking agent of claim 1.